The long-term objective of this proposal is to create more effective means by which to eradicate leukemia stem cells (LSCs). While multiple strategies have been described in the literature, finding approaches capable of broadly targeting LSC populations has remained elusive. We and others have described extensive intra-patient heterogeneity in human LSC populations, which we believe is an important factor to address in creating improved therapeutic regimens. To better understand the cellular and molecular drivers of LSC heterogeneity, we have conducted studies that demonstrate major differences in LSCs that occur purely as a function of their local tissue microenvironment. Particularly striking are differences observed between LSCs in bone marrow and adipose tissue, where upon localization to adipose tissue we observe a strong induction of fatty acid oxidation (FAO), reduced cell cycle activity and increased resistance to chemotherapy drugs. Thus, a central premise of the current application is that intra-patient LSC heterogeneity can arise due to extrinsic (i.e. microenvironmental) factors that vary as a function of anatomical site. Further, our data clearly imply a causal link between the microenvironment-induced metabolic state of LSCs and their sensitivity to drugs. The studies proposed herein are designed to identify and characterize key mechanisms that control LSC metabolism as a function of microenvironment. Lines of investigation will include analysis of cell intrinsic and extrinsic regulators of LSC metabolism.